Efficient synthesis of new indenopyridotriazine [4.3.3]propellanes and spiroindenopyridotriazine-4H-pyran derivatives

The pyrido[1,2,4]triazines as substrates, generated from 1,6-diaminopyridinone derivatives and ninhydrin, were reacted with malononitrile and CH-acids to afford a new library spiro[indeno[1,2-e]pyrido[1,2-b][1,2,4]triazine-7,5′-pyran]-1,3,6′-tricarbonitrile in ethanol at reflux condition in excellent yield. Also, novel indenopyridotriazine [4.3.3]propellanes were synthesized via the reaction of pyrido[1,2,4]triazine and N-methyl-1-(methylthio)-2-nitroethenamine (NMSM) by using of HOAc in ethanol. The important aspects of this protocol are the abundance of starting materials, mild conditions, structural diversity of products, excellent yields and easy isolation of products with no chromatographic technique.


Introduction
Fused nitrogen heterocycles are among the most special scaffolds in natural and synthetic products.Pyridotriazine derivatives are one of the signicant fused nitrogen heterocycles which have displayed a broad range of biological properties such as anti-avian inuenza virus (H 5 N 1 ), 1 anticancer, 2 antifungal, 3 anti-anxiety, anti-inammatory, 4 antibacterial, 5 antioxidant, 6 antimicrobial functions. 7Moreover, some examples of pyridotriazine can show optical 8 and corrosion inhibition properties. 91][12] Pyridotriazine moieties are commonly synthesized via heterocyclization reaction between 1,6-diaminopyridones and bifunctional electrophiles.As an unsymmetrical diamine, 1,6-diaminopyridone is a very active substrate for building diverse heterocyclic systems. 13][16] Diversity-Oriented Synthesis (DOS) is a new approach consists of synthetic methods to generating and developing new chemical diverse compounds libraries. 17DOS explores some promising new applications, that have the potential to signicantly advance studies in drug discovery and chemical biology, so that increase the biological outcome of the molecules. 18,19Spiro compounds are a specic category of heterocycles that are extensively found in many natural products and bioactive substances. 20Pyran core-containing compounds also have a great variety of pharmaceutical potentials and biological sensors. 21In this regard, spiro-4Hpyrans are signicant in organic synthesis because they have a wide spectrum of important biological effects that consist of anti-anaphylactic, antibacterial, 22 antitumor, antifungal, 23 and antirheumatic activities.0][31] Recently, numerous publications reported the synthesis of these compounds with indeno[1,2-b]quinoxalin (Scheme 1a), 32 indeno[2,1-c]pyridazine (Scheme 1b), 33 indolo[2,1b]quinazoline (Scheme 1c) 34 instead of active carbonyl compounds.6][37] To extend these works, we decided to use indeno [ 2,4]triazine as a main component in the reaction with malononitrile and CH-acids for building novel spiro-4Hpyrans (Scheme 1d).As a result, the fusion of the spiro-pyran system with the pyrido-triazine moiety could be as a privileged nucleus for many biological activities. 38We have successfully synthesized a series of compounds containing spiro-4H-pyrans attached to pyrido [1,2,4]triazine, which are completely new.
Nitrogen-containing propellane and analogs are remarkable models for the study of their synthesis, and have gained much consideration due to their pharmaceuticals. 39][42][43][44] (E)-N-Methyl-1-(methylthio)-2-nitroethenamine that have exibility and high reactivity has shown important attention as an ambiphilic synthon and suitable framework due to the attendance of push-pull system to synthesis of numerous heterocyclic compounds and mainly exist in natural and synthetic drugs. 45,46In continuation of our effort, by using pyrido-triazine as a main component and NMSM as an ambiphilic synthon, we also investigate an efficient synthesis of indenopyridotriazine [4.3.3]propellans in the presence of HOAc in ethanol (Scheme 1e).So far, there are no reports on the synthesis of these structures.
Using the results obtained from the optimized table, we succeeded in synthesizing a three-component one-pot proce- [1,2,4]  triazine derivatives 3a-g, malononitrile 4 and CH-acids 5 in EtOH under catalyst-free condition (Scheme 2).
The scope of the process is shown in Table 2.The desired compounds 6a-l were obtained in excellent yields in all cases and substituent with electron-donating/withdrawing of compounds 3a-g have not been effect in this reaction.
The structures of products 6a-l were elucidated from their IR, 1 H NMR, 13   a Reaction conditions were accomplished using 1, 2a, 3a, 4, 5a (1 mmol), catalyst (0.01 mmol), and solvent (10 mL).b Isolated yield based on 6a.To further expand the scope of these studies, we also tested nitroketene acetals as a 1,3-N,C di-nucleophilic precursor for the preparation of indenopyridotriazine [4.3.3]propellane.By using pyrido[1,2,4]triazine 3 (containing two C]N as 1,2-dielectrophilic sources) and NMSM 7 as a nitroketene N,C-acetal in the presence of HOAc as a catalyst, the [4.3.3]propellanesystem, was obtained.We used different solvents and catalysts for the optimization of this reaction.As a result, without catalyst, the yield was low, so the best conditions were achieved in EtOH in the vicinity of HOAc (10 mol%) at reux condition (Table 3).When we used compounds 3 containing electron-donating groups at high temperature conditions, the pyridone moiety was separated from the nal product (TLC and NMR evidence).Thus we could synthesize the [4.3.3]propellanesystem 8ad with good to high yields, when 1,6-diaminopyridone have electron-withdrawing groups.In all of these reactions, all products were obtained with high efficiency and good purity (Table 4).
The low solubility of products 6 and 8 in organic solvents signicantly simplied workup and purication of the products.The product is withdrawn from the reaction mixture by precipitation due to its low solubility in the solvent.However, the low solubility of these molecules made it difficult to evaluate their biological activities.Due to the low solubility of the products, NMR data could be obtained only for selected products.Just in case, it was not possible to obtain 13 C NMR data for compound 6e due to insolubility, while in other cases NMR data could be obtained by increasing the number of scans.

Conclusion
We have developed the synthesis of structurally diverse products from a simple reaction followed by cyclization steps and appendage diversity.This study describes a convenient protocol Scheme 3 Proposed mechanism for the formation of products 6.

Materials
All commercially available chemical compounds and other solvents in this study were purchased from Merck and Aldrich chemical companies.The NMR spectra for synthesized compounds were acquired using a Bruker DRX-300 AVANCE instrument (300 MHz for 1 H and 75.4 MHz for 13 C) with DMSOd 6 as the deuterated solvent.Chemical shis were reported in ppm (d) relative to the internal TMS, and the coupling constant (J) given in hertz (Hz).FT-IR spectra and melting points of all the compounds were measured with a Bruker Tensor 27 spectrometer and electrothermal 9100 apparatus, respectively.Mass spectra were given by an Agilent 5975C VL MSD with a Triple-Axis detector operating at an ionization potential of 70 eV.General procedure of the synthesis of pyrido [1,2,4]triazine compounds (3a-g).In a 10 mL round-bottomed ask mounted over a magnetic stirrer a mixture of ninhydrin 1 (2.0 mmol) and 1,6-diaminopyridinone derivatives 2 (2.0 mmol) and HOAc 10 mL was located.The contents were stirred magnetically in an oil-bath maintained at 50 °C (30-60 min).The progress of the reaction was monitored with TLC (using ethyl acetate-n-hexane 1 : 1), aer the reaction was completed; the reaction mixture was cooled to room temperature.Then, the solid was separated by ltration, washed twice times with water, and was subsequently washed with Et 2 O.The precipitate was dried in 130 °C to obtain crude product 3 without recrystallization. 48rocedure of the synthesis of spiroindenopyridotriazine-4Hpyran compounds (6a-l).The stoichiometric mixture of pyrido Scheme 1 Previous studies for synthesis of spiro-4H-pyrans.
C NMR and Mass spectral data.The 1 H NMR spectrum of 8a showed characteristic two signals of the N-H proton at d = 8.25 and 9.64 ppm (exchangeable with D 2 O).Aromatic

[ 1 ,Scheme 4
Scheme 4 Proposed mechanism for the formation of products 8.

Table 1
Optimization conditions for the generation of 6a a

Table 3
Optimization of reaction conditions for the synthesis of 8a

Table 4
Synthesis of indenopyridotriazine